Lung cancer is the leading cause of death from cancer in both American men and women with 147,000 estimated deaths in 1991. Although surgical treatment (and in the case of small cell lung cancer, chemotherapy and radiation) is effective in very early stage disease, only a small minority of patients present in this way, and even these maintain significant risk of recurrence in the five years following diagnosis. Although radiotherapy and chemotherapy can be applied to treat regionally extensive and metastatic disease, few major advances have been forthcoming in the past decade, and five year survival for patients with lung cancer overall remains quite low at 134. Thus, drug resistance represents a major obstacle to progress in the therapy of lung cancer. While in vitro models have identified the mechanisms operative in some forms of drug resistance, the causes of the resistance we encounter in the patient with lung cancer remain obscure. The overall objective of this proposal is to enhance insight into determinants of therapeutic response by evaluating pertinent in vitro correlates of drug sensitivity. We will focus on topotecan, the first topoisomerase I-targeted drug to be tested extensively in the clinic in the U.S. This drug arrives in the clinical arena with much already established regarding its mechanism of action and factors which influence cellular response. We plan prospective evaluation of critical parameters of topotecan sensitivity including topoisomerase I content, topotecan-induced cleavable complex formation, and proliferative fraction, in fresh tumor tissue of patients with lung cancer who will be treated with the drug. The long-term goal is to obtain significant correlations of these in vitro parameters with clinical outcome, both to predict response and understand resistance. However, due to the small number of patients we will be able to study initially, our immediate goals are to develop methodology, establish feasibility, and identify trends on which to base further study.
